Laboratory of Receptor Biology and Gene Expression, National Cancer Institute, NIH, Bethesda, MD, USA.
Laboratory of Molecular Gerontology, National Institute on Aging, NIH, Baltimore, MD, USA.
Nat Struct Mol Biol. 2019 Mar;26(3):213-219. doi: 10.1038/s41594-019-0192-3. Epub 2019 Mar 4.
The growth of telomerase-deficient cancers depends on the alternative lengthening of telomeres (ALT), a homology-directed telomere-maintenance pathway. ALT telomeres exhibit a unique chromatin environment and generally lack the nucleosome remodeler ATRX, pointing to an epigenetic basis for ALT. Recently, we identified a protective role for the ATRX-interacting macroH2A1.2 histone variant during homologous recombination and replication stress (RS). Consistent with an inherent susceptibility to RS, we show that human ALT telomeres are highly enriched for macroH2A1.2. However, in contrast to ATRX-proficient cells, ALT telomeres transiently lose macroH2A1.2 during acute RS to facilitate DNA double-strand break (DSB) formation, a process that is almost completely prevented by ectopic ATRX expression. Telomeric macroH2A1.2 is re-deposited in a DNA damage response (DDR)-dependent manner to promote homologous recombination-associated ALT pathways. Our findings thus identify the dynamic exchange of macroH2A1.2 on chromatin as an epigenetic link among ATRX loss, RS-induced DDR initiation and telomere maintenance via homologous recombination.
端粒酶缺陷型癌症的生长依赖于端粒的非经典延长（ALT），这是一种同源定向的端粒维持途径。ALT 端粒表现出独特的染色质环境，通常缺乏核小体重塑酶 ATRX，这表明 ALT 存在表观遗传基础。最近，我们发现 ATRX 相互作用的巨组蛋白 H2A1.2 变体在同源重组和复制应激（RS）期间具有保护作用。与对 RS 的固有易感性一致，我们表明人类 ALT 端粒高度富含巨组蛋白 H2A1.2。然而，与 ATRX 功能正常的细胞不同，在急性 RS 期间，ALT 端粒会短暂失去巨组蛋白 H2A1.2，以促进 DNA 双链断裂（DSB）的形成，而过表达 ATRX 几乎完全阻止了这一过程。端粒巨组蛋白 H2A1.2 以依赖于 DNA 损伤反应（DDR）的方式重新沉积，以促进与同源重组相关的 ALT 途径。因此，我们的发现确定了染色质上巨组蛋白 H2A1.2 的动态交换作为 ATRX 缺失、RS 诱导的 DDR 起始和通过同源重组维持端粒之间的表观遗传联系。
